Method of forcing the reverse transport of cholesterol from a body part to the liver while avoiding harmful disruptions of hepatic cholesterol homeostasis

Abstract

A pharmaceutical composition, kit, and method of forcing the reverse transport of cholesterol from peripheral tissues to the liver in vivo while controlling plasma LDL concentrations. The method includes the step of administering a therapeutically effective amount of a multiplicity of large liposomes comprised of phospholipids substantially free of sterol for a treatment period. The method optionally includes the step of periodically assaying plasma LDL concentrations with an assay during the treatment period to assess plasma atherogenic lipoprotein concentrations and obtain an atherogenic lipoprotein profile, and adjusting the administration in response to said profile. The large liposomes are dimensioned larger than fenestrations of an endothelial layer lining hepatic sinusoids in the liver so that the liposomes are too large to readily penetrate the fenestrations. The therapeutically effective amounts are in the range of about 10 mg to about 1600 mg phospholipid per kg body weight per dose. A pharmaceutical composition and related kit for mobilizing peripheral cholesterol and sphingomyelin that enters the liver of a subject consisting essentially of liposomes of a size and shape larger than fenestrations of an endothelial layer lining hepatic sinusoids in the liver is also provided.

I claim: 
     
       1. A method of controlling plasma LDL levels in vivo and reducing the sphingomyelin to phosphatidylcholine ratio in a cell membrane and cell aging, comprising: administering a therapeutically effective amount of a multiplicity of large liposomes comprised of phospholipids substantially free of sterol for a treatment period, said effective amount administered in a dosage, said dosage selected from a single dose and repeated doses.   
     
     
       2. The method in accordance with claim 1 in which the large, liposomes are of a size and shape larger than fenestrations of an endothelial layer lining hepatic sinusoids in a subject's liver, whereby said liposomes are too large to readily penetrate said fenestrations. 
     
     
       3. The method in accordance with claim 1 in which the therapeutically effective amount is in the range of about 10 mg to about 1600 mg phospholipid per kg body weight per dose. 
     
     
       4. The method in accordance with claim 1 in which the liposomes are given periodically. 
     
     
       5. The method in accordance with claim 1 in which the large liposomes are selected from the group consisting of uni-lamellar liposomes and multi-lamellar liposomes. 
     
     
       6. The method in accordance with claim 1 in which the liposomes have diameters larger than about 50 nm. 
     
     
       7. The method in accordance with claim 1 in which the liposomes have diameters larger than about 80 nm. 
     
     
       8. The method in accordance with claim 1 in which the liposomes have diameters larger than about 125 nm. 
     
     
       9. The method in accordance with claim 1 in which the step of administering is selected from the group of intravenous administration, intra-arterial administration, intramuscular administration, subcutaneous administration, transdermal administration, intraperitoneal administration, intrathecal administration, via lymphatics, intravascular administration, including administration into capillaries and arteriovenous shunts, rectal administration, administration via a chronically indwelling catheter, and administration via an acutely placed catheter. 
     
     
       10. The method in accordance with claim 1 further comprising the step of enhancing tissue penetration of a cholesterol acceptor and increasing extraction of tissue cholesterol and other exchangeable material by co-administration of an effective amount of a compound, said compound selected from the group consisting of a small acceptor of cholesterol and a drug that increases endogenous small acceptors of cholesterol. 
     
     
       11. The method in accordance with claim 1 further comprising periodically assaying said cells with an assay, said assay selected from the group consisting of an assay of sphingomyelin, an assay of phosphatidylcholine, an assay of membrane function, and an assay of cellular function. 
     
     
       12. The method in accordance with claim 11 in which the large liposomes are of a size and shape larger than fenestrations of an endothelial layer lining hepatic sinusoids in a subject's liver, whereby said liposomes are too large to readily penetrate said fenestrations. 
     
     
       13. The method in accordance with claim 11 in which the therapeutically effective amount is in the range of about 10 mg to about 1600 mg phospholipid per kg body weight per dose. 
     
     
       14. The method in accordance with claim 11 in which the liposomes are given periodically. 
     
     
       15. The method in accordance with claim 11 in which the large liposomes are selected from the group consisting of uni-lamellar liposomes and multi-lamellar liposomes. 
     
     
       16. The method in accordance with claim 11 in which the liposomes have diameters larger than about 50 nm. 
     
     
       17. The method in accordance with claim 11 in which the liposomes have diameters larger than about 80 nm. 
     
     
       18. The method in accordance with claim 11 in which the liposomes have diameters larger than about 100 nm. 
     
     
       19. The method in accordance with claim 11 in which the liposomes have diameters larger than about 125 nm. 
     
     
       20. The method in accordance with claim 11 in which the liposomes have diameters larger than about 150 nm. 
     
     
       21. The method in accordance with claim 11 in which the step of administering is selected from the group of intravenous administration, intra-arterial administration, intramuscular administration, subcutaneous administration, transdermal administration, intraperitoneal administration, intrathecal administration, via lymphatics, intravascular administration, including administration into capillaries and arteriovenous shunts, rectal administration, administration via a chronically indwelling catheter, and administration via an acutely placed catheter. 
     
     
       22. The method in accordance with claim 11 further comprising the step of enhancing tissue penetration of a cholesterol acceptor and increasing extraction of tissue cholesterol and other exchangeable material by co-administration of an effective amount of a compound, said compound selected from the group consisting of a small acceptor of cholesterol and a drug that increases endogenous small acceptors of cholesterol.